Papillomavirus transcription and DNA replication are regulation, at least in part, by products of the viral E1 and E2 open reading frames. To provide some insight into the mechanisms by which these proteins regulated the viral life-cycle, structural and functional analyses of the E1 and E2 proteins have been continued. It has been shown that a region of the E1 protein between residues 162 and 378 is important for origin-specific DNA binding. A large C-terminal domain of residues 162 to 605 is required for interaction with the E2 protein and for enhancement of E1 origin binding E2. The N-terminal 200 amino acids of the E2 protein forms a multifunctional domain important for transcription and regulation. In an attempt to separate these properties and to understand the mechanisms by which the E2 proteins function, an extensive mutational analysis of this domain has been carried out. A short peptide sequence that is responsible for nuclear targeting of the E2 proteins has been identified. This signal is contained within the region of the E2 DNA binding domain that forms a recognition helix for sequence specific DNA binding.